Bleeding resulting from factor VIII deficiency (hemophilia A) can occur in any tissue including the brain. Current treatments, including factor VIII (FVIII) replacement and recent novel therapeutics, focus primarily on joint health. In spite of advancements in treatment options, disabilities remain. People with hemophilia suffer from increased rates of mental health disorders compared to age and sex matched controls (45% vs. 18.5%). While significant progress has been made in prevention and treatment of hemophilia-related joint and muscle disease with current standards of care, there is a paucity of research in hemophilia A to understand, treat, or prevent brain disease. The long-term goal is to find diagnostic and treatment approaches that address the mechanism and structure of neurologic disease in hemophilia A. The objective of this proposal is to examine the role of FVIII deficiency on neurologic function and structure. The central hypothesis is that cerebral microbleeds and neuroinflammation lead to changes in brain structure, causing behavioral changes in hemophilia A mice. The rationale underlying this proposal is that completion will identify mechanisms causing poor neurologic outcomes in hemophilia A. The central hypothesis will be tested by pursuing three specific aims: Aim 1) Examine cerebral microbleeds and neuroanatomy phenotypes in hemophilia A mice. Aim 2) Investigate glial activation and neuroinflammation in hemophilia A mice. Aim 3) Identify the role of FVIII replacement in neuropsychiatric behavioral phenotypes in hemophilia A mice. We will pursue these aims using innovative quantitative neuroimaging and gene transfer techniques to evaluate brain structure and function in hemophilia animal model over time. The proposed research is significant because we will gain insights into the neuroanatomic changes and neuroinflammatory pathways impacted in a model of FVIII deficiency. The expected outcome of this work is that lack of FVIII will result in significant neurologic abnormalities. The results will have an important positive impact because they will establish a better understanding of the developing brain structure and function in FVIII deficiency, and long-term will improve cognitive, psychiatric, and quality of life outcomes for people with hemophilia A.